title: Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3.
abstract: OBJECTIVE
  Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified.
  
  
  OBJECTIVE
  To determine the molecular genetic cause of PPCD3.
  
  
  METHODS
  We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken.
  
  
  METHODS
  Ophthalmology department of a university hospital.
  
  
  METHODS
  Four Czech probands.
  
  
  METHODS
  Results of ophthalmological examination and direct sequencing of the ZEB1 coding region.
  
  
  RESULTS
  The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best-corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat ≥ 47.4 diopters [D] and steep ≥ 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm² to 1655/mm²). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele.
  
  
  CONCLUSIONS
  Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling.
authors.affiliation: Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic2Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Liskova
authors.forename: Michalis
authors.initials: M
authors.lastname: Palos
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Vincent
mesh_terms: D002452:Cell Count; D003317:Corneal Dystrophies, Hereditary / Q000175:diagnosis / Q000235:genetics*; D055954:Corneal Endothelial Cell Loss / Q000235:genetics*; D063171:Corneal Pachymetry; D019781:Corneal Topography; D004728:Endothelium, Corneal / Q000473:pathology*; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008967:Molecular Biology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014792:Visual Acuity; D055815:Young Adult; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1